Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department

ABSTRACT This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset.


Setting
The study was performed at University Hospital Virgen del Rocío (Spain).In our center, the microbiology department reports to the infectious diseases (ID) department all patients with positive blood cultures on a 24/7 basis.Patients with low-risk oBSI are routinely managed as outpatients, according to the criteria in Table 1.These criteria are regularly applied by the ID physician in charge of the ED area during weekdays and have been transmitted through educational sessions to the rest of the ID attendants to homogenize clinical management during on-call duty.

Objective
The objective of this study was to evaluate the safety of early oral ambulatory treatment of patients with oBSI.

Study population
Adult patients with blood cultures drawn at the ED between March 2020 and Novem ber 2021 were consecutively assessed.Two cohorts were followed up: (i) bacteremic febrile patients (BFPs), defined as those discharged from the ED with a febrile syndrome, in whom an oBSI was demonstrated and for whom the ID team recommended an outpatient management; and (ii) non-BFPs, defined as those discharged from the ED with a febrile syndrome, with negative blood cultures.Each BFP was matched with a non-BFP, according to these criteria: (i) first negative blood culture received in chronological order immediately after the BFP blood sample and (ii) the patient should have the same age as the BFP (±10 years).Patients in palliative care and contaminated cultures (defined by a unique positive set of blood cultures for a skin commensal organism) were excluded.

Endpoint
The primary endpoint was unplanned consultation in the emergency department (UCED) 30 days after the first ED visit.Secondary endpoints were all-cause 14-and 90-day mortality.

Statistical analysis
Differences between BFP and non-BFP were assessed through univariate analyses.As a sensitivity analysis, multivariate logistic regression was developed pooling both cohorts to determine factors associated with primary and secondary outcomes.Data were obtained through regional healthcare system database consultation.

Sample size
UCED rates of 17% have been reported for febrile patients discharged from EDs (7).Cohorts comparing bacteremic and non-bacteremic febrile hospitalized patients showed relative risk (RR) of up to 2 for unfavorable outcomes among patients with bacteremia (8).No studies were identified assessing outpatients.Using these data and assuming an alpha error of 0.05 and a power of 80%, we calculated a sample size of 206 patients (103 per group).

Results
During the study period, 193,400 patients were attended at the ED, with a global rate of UCED at 72 hours of 6.4%.Blood cultures were performed in 5,205 patients, and 777 were positive (14.9%).
Overall, 123 patients were diagnosed with oBSI.Outpatient management was recommended to 103 of these patients (83.7%).Ninety-nine of them (96.1%)finished their follow-up without hospitalization.No deaths were reported on day 14 after diagnosis, and the 90-day mortality rate was 1.9%.Clinical features of the 20 patients requiring hospital admission on oBSI diagnosis are detailed in Table S1.Baseline characteristics and outcomes of BFP and non-BFP are shown in Table 2, and data on specific antibiotic treatments and dosing are detailed in Table 3. Urinary infections predominated among BFP (73.8% vs 38.8%, P < 0.001), while non-focal fever was more frequent among non-BFP (8.7% vs 35%, P < 0.001), and empirical antibiotic treatment was started at ED discharge less frequently among the latter (92.2% vs 74.8%, P = 0.001).BFP and non-BFP presented low and similar rates of 30-day UCED (4.9 vs 3.9%, P = 0.73) and 14-day (0 cases) and 90-day (1.9 vs 8.7%, P = 0.058) mortality.
Multivariate analyses were performed for detecting factors independently related to unfavorable outcomes (Table S2).No variables were associated with increased UCED or 14-day mortality, including belonging to the cohort of bacteremic patients treated orally, the selection of any specific antibiotic class as definite therapy, or the use of an initial intravenous dose of antibiotics during the initial ED attendance.Malignancies (RR 6.69,

Discussion
Our study supports the safety of the oral, ambulatory treatment of patients with low-risk oBSI, whose outcomes were similar to other febrile patients without bacteremia routinely attended as outpatients.To our knowledge, this is the first comparative study assessing the safety of this approach for bacteremic infections.Randomized trials have unanimously shown the benefits of switching to oral treatments in stable patients with bacteremia (1), but the duration of previous intrave nous treatment varies widely across trials.Vandenbroucke et al. (10) found no effect on oral bioavailability of antibiotics during the acute phase of infection in non-critically ill patients.While there seems to be no good reasons for switching to intravenous therapy for low-risk bacteremic patients rapidly responding to oral treatment, admitting these patients for parenteral treatment after the diagnosis of oBSI has been the standard of care in many centers (4,5).Our results may challenge the current state of the art, suggesting that no minimum duration of intravenous lead-in is required in all patients with bacteremia and that switching to oral therapy can be performed as soon as clinical criteria are met.In fact, in our sample, the majority of bacteremic patients received no doses of intravenous antimicrobials at all.This strategy would be efficient and equally safe in the case of low-risk BSI, considering that 96.1% of these patients could avoid hospitalization.Our sample fairly represents patients with oBSI, since 103 of 123 patients could be treated orally, a datum that highlights the feasibility of this approach.However, an accurate assessment of patients' risk by ID experts would be essential to ensure its safety.Noticeably, we recorded no deaths during the first 14 days after oBSI diagnosis, even among those few patients requiring an unplanned admission.
Another remarkable aspect of our results is that most BFPs were managed with oral betalactams with good outcomes.Most studies performed to date advocate for quinolones as the preferential treatment for intravenous-to-oral switch due to their high bioavailability (1).Increased recurrence rates of bacteremia have been observed in some studies when betalactams were used (11), but this may be due to insufficient dosing of oral betalactams, as suggested by later works (12,13).In our center, high-dose oral betalactams are recommended as first-line empirical treatment due to quinolone resistance (Table 3) (14).Our results suggest that high-dose oral betalactams may be a good alternative for low-risk bacteremic patients, but our sample was not powered to assess differences between agents.
Our study has some limitations.First, despite performing sample size calculations, the cohort may be underpowered to detect small differences.However, the low incidence of complications in absolute terms supports our hypothesis.Second, there were imbalances between groups regarding a higher rate of non-focal fever and lower rates of empirical treatments among non-BFP.These differences probably respond to the requirement of negative blood cultures for non-BFP, which may have favored the inclusion of non-bacte rial fever in this group.Clinicians may have been reluctant to initiate empirical treatment for these cases.In our opinion, these differences define a profile of less-severe patients in the non-BFP cohort, which would reinforce our hypothesis.
In conclusion, the early oral, ambulatory treatment of low-risk bacteremic infections seems feasible and safe.These results provide a proof of concept for the efficacy of oral antibiotic therapy for bacteremia even from its onset and may enable outpatient care programs for these infections. )

5 .
Adequate accessibility to ensure close ambulatory follow-up and feasibility to return to the ED if needed.aoBSI produced by Staphylococcus aureus and Candida sp. are specifically precluded from outpatient management.

TABLE 1
Clinical criteria for patients with low-risk oBSI eligible for outpatient management 1.Early response to empiric antibiotic treatment: patient states to be asymptomatic or paucisymptomatic at first telephonic contact when the diagnosis of oBSI is informed.2.Active oral therapy options are available for the microorganism responsible for the oBSI.a 3.No clinical suspicion of a complicated source for oBSI, potentially requiring source control measures 4. No severe immunosuppression at oBSI diagnosis (current neutropenia, recent transplantation, etc.

TABLE 3
Antimicrobial agents and dosing a (Continued on next page)

TABLE 3
Antimicrobial agents and dosing a (Continued) These patients were prescribed at least one dose of empirical parenteral antibiotics according to the ED physician's clinical judgment during the first attention of the febrile syndrome, before knowing the diagnosis of bacteremia and before the ED discharge.
a ED, emergency department; IQR, interquartile range.b c These patients received dose adjustment due to chronic renal failure.